Yeh 2008 Budesonide Surf Act Ant Vehicle Prevent Cld

Early Intratracheal Instillation of Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants: A Pilot Study Tsu F. Yeh, Hong C. Lin, Chien H. Chang, Tien S. Wu, Bai H. Su, Tsai C. Li, Suma Pyati and Chang H. Tsai Pediatrics 2008;121;e1310-e1318; originally published online Apr 21, 2008; DOI: 10.1542/peds.2007-1973

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/121/5/e1310

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Early Intratracheal Instillation of Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants: A Pilot Study Tsu F. Yeh, MDa,b, Hong C. Lin, MDa, Chien H. Chang, PhDc, Tien S. Wu, PhDd,e, Bai H. Su, MDa, Tsai C. Li, PhDf, Suma Pyati, MDb, Chang H. Tsai, MDg a

Department of Pediatrics, College of Medicine, and fResearch Institute of Chinese Medicine, China Medical University, Taichung, Taiwan; Departments of cChemical Engineering and dChemistry, National Cheng Kung University, Tainan, Taiwan; eNational Research Institute of Chinese Medicine, Taipei, Taiwan; gDepartment of Biotechnology, Asian University, Wufeng, Taiwan; bDepartment of Pediatrics, John H. Stroger, Jr, Hospital of Cook County, Chicago, Illinois The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject

What This Study Adds

Budesonide-surfactant is a mixture to prevent CLD.

This study adds an alternative method to prevent CLD.

ABSTRACT OBJECTIVE. Budesonide is an inhaled steroid with a strong topical effect but with

minimal systemic effects; it has been effectively delivered to animal lungs using surfactant as a vehicle. The purposes of this study were to determine whether early intratracheal instillation of budesonide using surfactant as a vehicle would improve pulmonary status, reduce mortality, and reduce chronic lung disease morbidity. PATIENTS AND METHODS. We conducted a prospective, randomized blind trial in 116 very low birth weight infants (⬍1500 g) who had severe radiographic respiratory distress syndrome and required mechanical ventilation with fraction of inspired oxygen ⱖ0.6 shortly after birth: 60 were in the treated group (intratracheal instillation of a mixture of 0.25 mg/kg of budesonide and 100.00 mg/kg of survanta, every 8 hours) and 56 were in the control group (100 mg/kg of survanta only, every 8 hours). The end point assessment was the number of infants who would die or develop chronic lung disease at 36 weeks’ postconceptional age. RESULTS. Infants in the treatment group required significantly lower mean airway

pressure on day 1 and day 3 and had significantly lower oxygen index and PCO2 during the first 3 days than infants in the control group. More infants were extubated in the treatment group than controls at 1 and 2 weeks. The combined outcome of deaths or chronic lung disease was significantly lower in the treatment group than in the control group (19 of 60 vs 34 of 56). No clinically significant adverse effects were observed during the study. CONCLUSIONS. This pilot study indicated that early postnatal intratracheal instillation of

budesonide using surfactant as vehicle significantly improved the combined outcome of death or chronic lung disease in small premature infants without causing immediate adverse effects. The results are encouraging, and a large sample multicenter trial is warranted.

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1973 doi:10.1542/peds.2007-1973 This study was presented in part at the annual meeting of the Pediatrics Academic Societies; April 30, 2006; San Francisco, CA. This trial has been registered at www.clinicaltrials.gov (identifier NCT001446497). Key Words budesonide, survanta, chronic lung disease Abbreviations CLD— chronic lung disease RDS—respiratory distress syndrome FIO2—fractional inspired oxygen CPAP— continuous positive airway pressure IMV—intermittent mandatory ventilation AUC—area under the plasma concentration-time curve MAP—mean airway pressure OI— oxygen index Accepted for publication Nov 14, 2007 Address correspondence to Tsu F. Yeh, MD, Department of Pediatrics, College of Medicine, China Medical University, 91 Hsieh Shih St, Taichung, Taiwan; or Department of Pediatrics, John H. Stroger Hospital of Cook County, 1901 W Harrison St, Chicgo, IL 60612. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2008 by the American Academy of Pediatrics

C

HRONIC LUNG DISEASE (CLD) continues to be the most important complication in premature infants after mechanical ventilation. Various evidence indicates that pulmonary inflammation plays an important role in the pathogenesis of CLD. Glucocorticoids suppress the lung inflammation and have been used to treat or prevent CLD1–4 for more than a decade; however, because of the systemic adverse effects,5–7 glucocorticoids are not recommended for routine use. Nevertheless, the local beneficial effects of systemic glucocorticoid on the respiratory tract are well documented.8–10 One alternative to systemic administration is delivery of glucocorticoids by inhalation11–17 or by intratracheal instillation. However, delivery of inhaled glucocorticoids in preterm infants is technically difficult, and its effectiveness has been shown to be limited.11–17 Direct intratracheal instillation of glucocorticoid alone has also not been shown to be effective.18 To achieve a better local effect of steroid on the airway, a new method of delivery is, therefore, proposed.

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TABLE 1 Dynamic Surface Tension Behavior of Survanta, Budesonide, and Their Mixtures System

S suspension

B suspension Mixed S/B suspension

Phospholipid Concentration, mg/mL

Budesonide Concentration, mg/mL

⌼e, mN/m

⌼min, mN/m

⌼max, mN/m

25.00 12.50 1.00 — — 12.50 1.00

— — — 0.50 0.25 0.25 0.25

19 21 22 31 33 20 28

⫺0 ⫺0 5 27 29 ⫺0 20

46 51 49 47 49 41 45

S indicates survanta; B, budesonide; —, mN/m, milli-Newton/meter; ⌼e, equilibrium surface tension; ⌼min, minimum surface tension; ⌼max, maximum surface tension.

Surfactant is now routinely used in preterm infants with respiratory distress syndrome (RDS). After surfactant instillation, there was a rapid distribution of surfactant to the lung periphery,19,20 probably resulting from a dragging force created by surface tension gradient (Marangoni effect) between the instilled surfactant and the airway liquid.21 This dragging force would facilitate the instilled medication, such as steroid or antibiotics, in reaching the periphery of the lungs.22,23 Budesonide is an inhaled glucocorticoid commonly used in children with asthma. It induces a high local anti-inflammatory effect24 and undergoes an extensive biotransformation in the liver to metabolites of low glucocorticoid activity.25–27 We, therefore, hypothesized that intratracheal instillation of budesonide using surfactant as a vehicle would facilitate the delivery of budesonide and improve pulmonary outcome without causing significant adverse effects. Based on this hypothesis, we conducted a double-blind randomized trial. The purposes of the study were as follows: (1) to investigate whether early intratracheal instillation of a budesonide-surfactant mixture within 4 hours after birth improved the respiratory status in preterm infants with severe RDS; (2) to analyze whether improvement in respiratory status increased survival rate or decreased CLD morbidity; and (3) to measure the associated adverse effects. MATERIALS AND METHODS During an 18-month period from September 1, 2004, to February 28, 2006, all of the infants with birth weights of ⬍1500 g and with RDS were eligible for the study. The selection criteria for the study were as follows: (1) severe radiographic RDS requiring mechanical ventilation within 4 hours after birth; (2) requirement of fractional inspired oxygen (FIO2) of ⱖ0.6; and 3) absence of severe congenital anomalies and lethal cardiopulmonary disorders. We believed that these infants were at high risk of developing CLD. The study was approved by the scientific and institutional review board of the hospital; informed consent was obtained from the parent of each infant. Sample Size Calculation Our previous experience has indicated that ⬃60% of infants fulfilling the inclusion criteria would die or develop CLD.1 Using the sample size table of Fleiss28 and making some plausible estimates of the proportion of

infants in the budesonide-treated group whose conditions would improve, we calculated that the inclusion of ⬃60 infants in each group would give a high probability of detecting the hypothesized difference in combined outcome of death or CLD. Considering the limited number of infants that could be included for the study in our hospital, we hypothesized that 60% in the control group and 30% in the budesonide-treated group (50% improvement) would either die or develop CLD. If we permitted a 5% chance of type 1 error and a 20% chance of type 2 error, the number required in each group would be 54. Allowing 10% for attrition and exclusions from the final study group, 60 was considered a safe target number for each group. Control and Budesonide Regimens, Dosages, and Randomized Procedures Budesonide (Pulmicort nebulising suspension, Astra Zeneca, Lund, Sweden), a dehalogenic glucocorticoid, and survanta (Abbott, Columbus, OH), a mixture of phospholipids and hydrophobic proteins, both are stable compounds. They are unlikely to generate chemical reactions when mixed immediately before administration. We did not observe any apparent change in the mixture for ⱖ30 to 60 minutes before we started the in vitro study. However, budesonide, having a ring structure with certain degrees of unsaturation and branching, may possess the capacity to interfere with the surfactant monolayer structure at the air-liquid interface.29 We, therefore, conducted an in vitro study to investigate the competitive absorption behavior of a survanta-budesonide suspension before the study was conducted in neonates. The dynamic surface tension behavior of survanta, budesonide, and their mixtures was evaluated by pulsating the air-liquid interfaces at a rate of 20 cycles per minute at 37°C (Surfactometer, Amherst Electronics, Buffalo, NY). When a survanta suspension was mixed with an equal volume of a budesonide suspension, with a concentration ratio of 12.50:0.25 mg/mL, the dynamic surface activity of the survanta suspension was minimally affected (Table 1). We, therefore, concluded that when survanta and budesonide were used clinically at the same time at a concentration ratio of 50:1 or more, budesonide would not reduce the ability of survanta to reduce surface tension.30 Based on these results, we calculated the dosage for neonates. PEDIATRICS Volume 121, Number 5, May 2008

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The numbers 1 through 120 were randomly assigned to the control and the budesonide-treated group at a ratio of 1:1 by drawing from a sealed envelope. The concealed randomization scheme was generated by a computer with permuted blocks in random sizes of 2, 4, 6, and 8 to maintain balance. In each successive 40 numbers, 20 were assigned to the treatment group and 20 to the control group. This was to ensure that the independent observer (Dr Hsin Y. Hsieh, Department of Pediatrics, China Medical University, Taichung, Taiwan) would be able to detect a trend, such as an unexpected complication, as early as possible; the study could then be modified to preserve the best interests of the infants. When the first dose of survanta was to be prescribed, the independent observer would open the assignment list to determine whether budesonide should be dispensed. If a control was indicated, a syringe containing survanta (100 mg or 4 mL/kg) only would be prepared, and if budesonide was indicated, a syringe containing survanta (100 mg or 4 mL/kg) and budesonide (0.25 mg or 1.00 mL/kg) would be prepared. This dosage was chosen based on experiences in children with asthma that inhaled 0.5 to 1.0 mg twice daily of budesonide was effective and did not suppress adrenal function.31 Our previous study also showed that intratracheal instillation of 0.25 mg/kg of budesonide did not increase adverse effects as compared with the control.18 This dosage of budesonide would provide the concentration ratio between survanta and budesonide of ⬎50:1. The syringe was covered with tape so that the caretaker was not aware of the volume and content of the syringe. Before intratracheal instillation, the syringe was gently vortexed. Each dose was divided into 4 aliquots, administered to the infant in 4 different positions: right and left lateral, head up, and head down. Surfactant was given in our NICU as rescue therapy; the first dose was usually given shortly after admission to the NICU. Repeated doses were given every 8 hours for both treated and control infants until the infant required ⬍0.4 of FIO2 or until the infant was extubated. Diagnosis and Treatment of RDS RDS was diagnosed according to clinical and radiographic features. A protocol for the treatment of RDS was followed in each infant. Blood gas samples were obtained through an umbilical arterial catheter, a peripheral artery, or occasionally by the capillary method at 8:00 to 10:00 AM each day. The criteria for initiating continuous positive airway pressure (CPAP), intermittent mandatory ventilation (IMV), and high-frequency oscillatory ventilation were described previously.1 Essentially, the infant would be placed on CPAP if the arterial or arterialized capillary PO2 was ⬍50 mm Hg with FIO2 ⬎0.4 or apnea. Intermittent mandatory ventilation was initiated if there was failure to respond to CPAP or the PO2 was ⬍50 mm Hg, with FIO2 ⬎0.6 or PCO2 ⬎60 mm Hg. High-frequency oscillatory ventilation was initiated if arterial PO2 was ⬍50 mm Hg, with FIO2 at 1.0, or if the IMV rate was ⱖ60 per minute. Nitric oxide was rarely given in our premature infants. Weaning from mechanical ventilation started as soon as there was ime1312

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provement in blood gases and in clinical conditions. The weaning process followed a protocol described previously.1 Once the peak ventilatory pressure was ⬍25 cm H2O, the FIO2 was decreased, with a 5% reduction each time. When the FIO2 had been reduced to 0.4, attempts were made to speed up the weaning process by decreasing the rate. Once the rate had been decreased 5 to 10 per minute, CPAP was initiated. The CPAP pressure was then gradually reduced until it reached 2 cm H2O. If the blood gas values remained appropriate, extubation was initiated. Total fluid intake was adjusted to 60 to 80 mL/kg per day on the first postnatal day and increased daily to 150 mg/kg per day by 2 to 3 weeks and onward, subjected to patient’s condition. The use of antibiotics was judged by the attending physician based on prenatal history, perinatal events, and clinical features of the infant. Blood cultures were obtained from infants suspected of having developed infection if the infant had signs of lethargy or had increases in immature neutrophils or elevated C-reactive protein levels.32 A dopamine (2–5 ␮g/kg) drip was started if the infant had unstable blood pressure. Indomethacin was given to infants who had significant patent ductus arteriosus. Postnatal dexamethasone was reserved only for infants who had severe CLD and intractable respiratory failure. In such cases, a short course of dexamethasone, 0.25 mg/kg every 12 hours for 3 to 5 doses, was given at the discretion of the individual attending. CLD was diagnosed at 36 weeks’ postconceptional age if the infant continuously had respiratory distress requiring supplemental oxygen therapy since birth and abnormal chest radiographic findings. Budesonide and 16␣-Hydroxyprednisolone Assay The plasma levels of cortisol, budesonide, and its metabolite, 16␣-hydroxyprednisolone, were determined in the first 30 infants by liquid chromatography tandem mass spectrometry33 at 30 minutes and 1, 2, 4, and 8 hours after intratracheal instillation. The plasma clearance, terminal half-life, and area under the plasma concentration-time curve (AUC) of budesonide were calculated. Statistics The data were analyzed by a statistician (Dr Li) using an SAS computer system (SAS Institute, Inc, Cary, NC) with the combined incidence of death or CLD as the primary outcome variable. Analysis of variance and, when appropriate, the t test were used to make group comparisons for continuous variables. The ␹2 test was used to compare groups with respect to categorical variables. Except where indicated, values are specified as means ⫾ 1 SD. RESULTS During the 18-month study period, a total of 172 infants with RDS were admitted to the NICU; of these, 135 fulfilled the inclusion criteria. Consents were obtained from the parents of 120 of the infants. However, 4

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Number of RDS infants admitted to NICU

172

Number of infants (<1500 gm) with severe RDS

135

requiring mechanical ventilation within 4 hours after birth and FIO2 > 0.6 15 refused to participate 2 died shortly after birth 2 multiple congenital anomalies

116

60 Treated

Number of infants who met the criteria for study

56 Control

FIGURE 1 Disposition of the patients studied.

infants were excluded because of death (n ⫽ 2) shortly after birth and multiple congenital anomalies (n ⫽ 2). Therefore, the total number of infants included for the study was 116: 60 in the budesonide-treated group and 56 in the control group (Fig 1). Table 2 lists the clinical and laboratory characteristics in the perinatal period and at the time of study entry. There was no significant difference between the groups in any of these variables. The mean postnatal age of infants when they received the first dose of budesonide was 2.1 ⫾ 2.2 hours. Pulmonary Status As shown in Fig 2, infants in the treatment group had better pulmonary status than those the control group with respect to the following: lower mean airway pressure (MAP) on day 1 (5.7 ⫾ 1.8 cm H2O vs 6.7 ⫾ 1.8 cm H2O; P ⫽ .003) and day 3 (5.9 ⫾ 2.1 cm H2O vs 7.1 ⫾ 3.6 cm H2O; P ⫽ .039); lower FIO2 on day 1 (0.43 ⫾ 0.19 vs 0.52 ⫾ 0.19; P ⫽ .021) and day 2 (0.40 ⫾ 0.14 vs 0.47 ⫾ 0.19; P ⫽ .049); lower oxygen index (OI) on day 1 (5.6 ⫾ 5.6 vs 9.9 ⫾ 9.2; P ⫽ .005), day 2 (4.9 ⫾ 5.2 vs 10.4 ⫾ 8.9; P ⬍ .001), and day 3 (5.1 ⫾ 4.4 vs 8.6 ⫾ 6.0; P ⬍ .001); lower PCO2 on day 1 (41.1 ⫾ 8.6 mm Hg vs 49.2 ⫾ 9.8 mm Hg; P ⬍ .001), day 2 (42.1 ⫾ 11.0 mm Hg vs 47.6 ⫾ 12.1 mm Hg; P ⫽ .012), and day 3 (43.0 ⫾ 9.4 mm Hg vs 48.0 ⫾ 8.9 mm Hg; P ⫽ .004); and higher PO2 on day 1 (68.0 ⫾ 22.1 mm Hg vs 56.1 ⫾ 22.3 mm Hg; P ⫽ .027) and day 2 (65.3 ⫾ 23.1 mm Hg vs 55.1 ⫾ 22.2 mm Hg; P ⫽ .017). Among the survivors, more infants in the treatment group were extubated during weeks 1 and 2 than those in the control group (24 of 56 vs 5 of 45, P ⫽ .001 and 27 of 55 vs 9 of 40, P ⫽ .015, respectively). Significantly more infants in the treatment group than in the control group received only 1 dose of surfactant (37 of 60 vs 20 of 56, P ⫽ .015). Five infants in the budesonide group

TABLE 2 Clinical and Laboratory Characteristics in the Perinatal Period and at Time of Study Entry Characteristics

Budesonide (n ⫽ 60)

Control (n ⫽ 56)

Birth weight, mean ⫾ SD, g Gestational age, mean ⫾ SD, wk Appropriate for gestational age/small for gestational age, n/n Gender, male/female, n/n Type of delivery, n Cesarean section Vaginal Apgar score, n 1 min ⱕ3 4–6 ⬎6 5 min ⱕ3 4–6 ⬎6 Prenatal steroid, n Age of study, mean ⫾ SD, h Fluids intake, mean ⫾ SD, mL/kg per d IMV, mean ⫾ SD Rate per min Peak inspiratory pressure/positive end expiratory pressure, cm H2O MAP, cm H2O FIO2, mean ⫾ SD PO2, mean ⫾ SD, mm Hg PCO2, mean ⫾ SD, mm Hg pH, mean ⫾ SD Base deficit, mean ⫾ SD, mEq/L Blood pressure, mean ⫾ SD, mm Hg Systolic Diastolic Hematocrit, mean ⫾ SD, %

881 ⫾ 245 26.4 ⫾ 2.2 42/18

919 ⫾ 272 26.7 ⫾ 2.3 35/21

31/29

29/27

35 25

32 24

30 27 3

25 26 5

2 6 52 46 2.1 ⫾ 2.2 67.8 ⫾ 30.4

0 3 53 42 2.1 ⫾ 1.4 71.8 ⫾ 21.7

32 ⫾ 6 14 ⫾ 3/4 ⫾ 1

33 ⫾ 5 15 ⫾ 3/4 ⫾ 1

6.0 ⫾ 1.1 0.74 ⫾ 0.18 76.5 ⫾ 34.8 52.1 ⫾ 10.8 7.21 ⫾ 0.14 8.1 ⫾ 0.8

6.7 ⫾ 1.7 0.73 ⫾ 0.15 80.5 ⫾ 38.2 56.3 ⫾ 16.2 7.20 ⫾ 0.11 8.3 ⫾ 4.3

45.2 ⫾ 10.0 28.7 ⫾ 7.6 41.5 ⫾ 6.8

45.5 ⫾ 8.5 28.1 ⫾ 8.0 42.0 ⫾ 6.0

and 7 in the control group received dexamethasone therapy during hospitalization. Mortality and CLD Morbidity Ten infants (16.6%) died in the budesonide-treated group, and 18 (32.1%) died in the control group (P ⫽ .084). Nine infants in the budesonide-treated group and 16 in the control group developed CLD (P ⫽ .121). The total number of infants who either died or developed CLD in the budesonide-treated group (19 [31.7%]) was significantly lower than that in the control group (34 [60.7%]; P ⫽ .003). The proportion of infants who survived without CLD was significantly greater in the budesonide-treated group (41 of 50 [82%]) than in the control group (22 of 38 [58%] P ⫽ .025). The causes of death were judged by terminal clinical events: intractable respiratory failure (treatment versus control; 2 of 10 vs 9 of 18; P ⫽ .226); severe intraventricular hemorrhage (2 of 10 vs 2 of 18); or sepsis and other causes (6 of 10 vs 7 of 18). The mean duration of high-oxygen therapy (FIO2 ⬎0.4) was significantly shorter in the budesonidetreated group than in the control group (5.8 ⫾ 10.2 vs PEDIATRICS Volume 121, Number 5, May 2008

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FIGURE 2 The changes of MAP, FIO2, OI, PO2, PCO2, and pH during the first 14 days after starting the study. The parentheses indicate the number of infants remaining on a ventilator. Infants in the treatment group had lower MAP on day 1 (P ⫽ .003) and day 3 (P ⫽ .039); lower FIO2 on day 1 (P ⫽ .021) and day 2 (P ⫽ .049); lower OI on day 1 (P ⫽ .005), day 2 (P ⬍ .001), and day 3 (P ⬍ .001); and lower PCO2 on day 1 (P ⬍ .001), day 2 (P ⫽ 0.012), and day 3 (P ⫽ .004); and higher PO2 on day 1 (P ⫽ .027) and day 2 (P ⫽ .017).

12.9 ⫾ 16.2 days; P ⫽ .047). The total duration of IMV and the duration of supplemental oxygen therapy and hospitalization were all shorter in the treatment group, but the difference between the groups was not statistically significant (14.6 ⫾ 19.2 vs 19.5 ⫾ 23.5 days, P ⫽ .224; 44.8 ⫾ 25.6 vs 52.1 ⫾ 36.9 days, P ⫽ .225; and 50.3 ⫾ 33.2 vs 63.1 ⫾ 42.3 days, P ⫽ .075, respectively). Adverse Effects A summary of the possible adverse effects is shown in Table 3. The treatment group had a significantly higher systolic blood pressure on day 3 (P ⬍ .001) and day 7 (P ⫽ .032), higher diastolic blood pressure on day 3 (P ⫽ .015) and day 5 (P ⫽ .028), and higher serum potassium on day 2 (P ⫽ .041) than the control group; however, there were no significant differences in other variables between the groups during the study. The 2 groups were comparable in fluid intake and in body weight, length, and head circumference during the study. The incidences of intraventricular hemorrhage (at or more than e1314

YEH et al

grade 2; 6 of 60 vs 7 of 56; P ⫽ .946), patent ductus arteriosus (36 of 60 vs 32 of 56; P ⫽ .264), retinopathy of prematurity (all grades, 25 of 60 vs 21 of 56; P ⫽ .798), and clinical infection and/or sepsis (6 of 60 vs 5 of 56; P ⫽ .94) were comparable between the groups. Budesonide and 16␣-Hydroxyprednisolone Assay Completed blood sample for pharmacokinetic study was obtained in 22 infants: 10 in the treated group and 12 in the control group. The plasma concentration-time curve of the 10 budesonide-treated infants is shown in Fig 3. The peak plasma concentration of budesonide was seen at ⬃30 minutes, and the peak of 16␣-hydroxyprednisolone was at 2 hours after budesonide instillation. The terminal half-life was 4.13 hours. The AUC of budesonide from time 0 to 8 hours was 115.73 ng/mL. Assuming that the blood volume in preterm infants was 80 mL/kg, we calculated that the total amount of budesonide in the blood during the first 8 hours was 9258 ng. This would consist of ⬃4% of budesonide instilled into

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Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control Budesonide Control

Systolic blood pressure, mm Hg

a Data

2 47.2 ⫾ 7.9 45.2 ⫾ 8.7 30.3 ⫾ 8.7 28.8 ⫾ 8.5 60.2 ⫾ 29.5 66.5 ⫾ 40.5 23.1 ⫾ 8.6 23.2 ⫾ 4.6 135 ⫾ 7 135 ⫾ 7 5.2 ⫾ 0.9a 4.8 ⫾ 0.9 282 ⫾ 39 286 ⫾ 17 17.4 ⫾ 15.1 15.2 ⫾ 12.0 4.5 ⫾ 2.5 4.7 ⫾ 3.1 53.4 ⫾ 62.1 66.5 ⫾ 63.1 — — — — — — — —

1 46.3 ⫾ 6.6 45.4 ⫾ 9.7 30.5 ⫾ 6.2 29.8 ⫾ 9.2 76.8 ⫾ 38.9 68.2 ⫾ 32.3 15.8 ⫾ 6.0 18.4 ⫾ 4.9 135 ⫾ 8 134 ⫾ 7 5.0 ⫾ 0.9 4.9 ⫾ 1.1 281 ⫾ 17 282 ⫾ 12 18.6 ⫾ 25.7 14.0 ⫾ 10.8 6.8 ⫾ 3.4 5.1 ⫾ 4.1 99.6 ⫾ 97.1 81.3 ⫾ 89.4 67.8 ⫾ 30.3 71.9 ⫾ 21.7 881.0 ⫾ 244.5 919.4 ⫾ 272.2 33.2 ⫾ 4.0 34.2 ⫾ 4.3 23.2 ⫾ 2.4 23.6 ⫾ 2.2

show the significant difference between the groups (see text).

Head circumference, cm

Length, cm

Body weight, g

Total fluid intake, mL/kg per d

Eosinophile, ⫻10 9/L

Lymphocyte, ⫻10 9/L

White blood cell, ⫻10 9/L

Serum osmality, mOsm

Serum potassium, mEq/L

Serum sodium, mEq/L

Serum urea nitrogen, mg %

Glucose, mg %

Diastolic blood pressure, mm Hg

Therapy

Variable

TABLE 3 Possible Adverse Effects After Budesonide Therapy

54.9 ⫾ 9.1 50.9 ⫾ 10.7 32.1 ⫾ 9.7 29.7 ⫾ 9.8 82.6 ⫾ 30.7 88.1 ⫾ 48.6 21.5 ⫾ 14.0 30.2 ⫾ 23.4 138 ⫾ 7 138 ⫾ 7 4.1 ⫾ 0.6 4.3 ⫾ 0.7 281 ⫾ 15 290 ⫾ 33 — — — — — — — — — — — — — —

55.3 ⫾ 9.7 52.0 ⫾ 11.2 34.8 ⫾ 9.6a 30.8 ⫾ 9.8 68.7 ⫾ 30.4 78.6 ⫾ 30.1 28.9 ⫾ 15.7 27.6 ⫾ 16.6 140 ⫾ 6 141 ⫾ 8 4.2 ⫾ 0.7 4.5 ⫾ 0.8 294 ⫾ 24 293 ⫾ 18 15.7 ⫾ 20.1 12.4 ⫾ 4.4 4.9 ⫾ 2.5 3.50 ⫾ 2.1 331 ⫾ 450 201 ⫾ 150 119.1 ⫾ 16.0 111.6 ⫾ 15.5 750.5 ⫾ 266.5 830.4 ⫾ 245.5 34.0 ⫾ 4.2 35.0 ⫾ 3.3 23.2 ⫾ 2.2 23.5 ⫾ 2.3 50.2 ⫾ 7.1 45.6 ⫾ 8.7 32.7 ⫾ 6.0a 29.7 ⫾ 7.1 60.0 ⫾ 28.4 64.1 ⫾ 24.9 29.6 ⫾ 9.9 25.8 ⫾ 8.6 140 ⫾ 10 140 ⫾ 8 4.6 ⫾ 0.8 4.6 ⫾ 1.0 297 ⫾ 14 294 ⫾ 15 12.6 ⫾ 8.7 12.7 ⫾ 14.5 4.3 ⫾ 2.8 3.7 ⫾ 2.1 68.5 ⫾ 35.1 83.1 ⫾ 80.2 — — — — — — — — a

7

a

Age, Mean ⫾ SD, d 5

3 53.2 ⫾ 7.5 53.7 ⫾ 11.8 32.8 ⫾ 7.2 31.7 ⫾ 10.8 95.0 ⫾ 34.0 105.6 ⫾ 36.2 24.8 ⫾ 21.7 20.3 ⫾ 17.4 136 ⫾ 8 136 ⫾ 5 4.3 ⫾ 0.5 4.4 ⫾ 0.7 275 ⫾ 50 285 ⫾ 21 — — — — — — 128.1 ⫾ 24.4 137.8 ⫾ 16.5 786.0 ⫾ 245.1 860.2 ⫾ 263.5 34.1 ⫾ 3.6 35.5 ⫾ 2.8 22.6 ⫾ 2.6 23.3 ⫾ 2.2

10 58.9 ⫾ 6.8 56.9 ⫾ 7.5 35.5 ⫾ 8.5 34.1 ⫾ 7.4 100.8 ⫾ 46.2 111.6 ⫾ 33.7 25.9 ⫾ 16.9 19.5 ⫾ 20.1 135 ⫾ 5 135 ⫾ 4 4.2 ⫾ 0.6 4.3 ⫾ 0.6 283 ⫾ 24 289 ⫾ 19 13.8 ⫾ 11.2 11.3 ⫾ 9.8 4.4 ⫾ 2.1 4.5 ⫾ 3.8 317 ⫾ 360 414 ⫾ 230 135.4 ⫾ 13.2 135.9 ⫾ 12.7 780.8 ⫾ 238.8 862.9 ⫾ 279.9 34.6 ⫾ 4.3 35.6 ⫾ 3.4 22.6 ⫾ 2.2 23.1 ⫾ 2.4

14

59.0 ⫾ 7.7 58.8 ⫾ 7.4 35.1 ⫾ 7.7 35.4 ⫾ 7.9 99.4 ⫾ 30.5 101.2 ⫾ 38.4 21.3 ⫾ 21.6 17.7 ⫾ 18.0 134 ⫾ 6 135 ⫾ 5 3.9 ⫾ 0.6 4.1 ⫾ 0.6 276 ⫾ 12 274 ⫾ 14 — — — — — — 128.6 ⫾ 22.7 135.0 ⫾ 26.1 820.0 ⫾ 274.3 902.1 ⫾ 237.4 34.6 ⫾ 3.1 35.6 ⫾ 4.3 22.7 ⫾ 1.7 22.9 ⫾ 2.1

21

57.8 ⫾ 10.4 60.3 ⫾ 9.9 35.8 ⫾ 8.9 37.0 ⫾ 8.8 99.5 ⫾ 30.8 94.3 ⫾ 26.8 16.0 ⫾ 18.1 13.2 ⫾ 8.8 131 ⫾ 7 132 ⫾ 5 4.1 ⫾ 0.7 4.2 ⫾ 0.6 266 ⫾ 10 267 ⫾ 8 12.5 ⫾ 9.8 11.2 ⫾ 8.8 3.9 ⫾ 2.9 4.3 ⫾ 3.2 250 ⫾ 210 281 ⫾ 186 148.2 ⫾ 23.6 150.2 ⫾ 28.1 890.7 ⫾ 290.5 980.5 ⫾ 382.4 35.3 ⫾ 3.9 36.4 ⫾ 4.1 22.7 ⫾ 2.8 23.2 ⫾ 3.0

28

Plasma concentration, ng/ml

100

♦ Budesonide ■ 16-α - hydroxyprednisolone (Semilog scale)

10

1

0

1

2

3

4

5

6

7

8

9

Time after medication, hours FIGURE 3 The plasma concentration of budesonide and its metabolite 16␣-hydroxyprednisolone at 30 minutes and 1, 2, 4, and 8 hours after intratracheal instillation, expressed in semilogarithm paper.

the lung. Two infants who received prenatal steroid therapy were excluded from cortisol-level analysis. There were no significant differences between the treatment and control groups in plasma cortisol levels (6.1 ⫾ 4.3 ng/mL vs 8.5 ⫾ 7.8 ng/mL, P ⬎ .1 at 30 minutes; 8.2 ⫾ 7.8 ng/mL vs 7.8 ⫾ 7.7 ng/mL, P ⬎ .1 at 1 hour; 8.0 ⫾ 6.5 ng/mL vs 7.7 ⫾ 9.7 ng/mL, P ⬎ .1 at 2 hours; 6.3 ⫾ 7.5 ng/mL vs 9.9 ⫾ 11.8 ng/mL, P ⬎ .1 at 4 hours; 8.3 ⫾ 8.0 ng/mL vs 12.6 ⫾ 12.5 ng/mL, P ⬎ .1 at 8 hours). DISCUSSION The present study demonstrated that early intratracheal instillation of budesonide using surfactant as a vehicle significantly improved the pulmonary status, reduced the combined incidence of CLD or death, and increased the number of survivors without CLD. There were no immediate and clinically significant adverse effects associated with this therapy. Using surfactant as a vehicle to deliver steroid to the lungs has been investigated by Fajardo et al,22 Nimmo et al,34 and Chen et al35 in various small animal models. Nimmo et al34 showed that, with a certain concentration ratio, the addition of dexamethasone to survanta did not alter the surface properties of the surfactant. After intratracheal instillation to rats, radiolabeled dexamethasone in survanta was well distributed throughout all 4 lobes of the lungs, with a concentration gradient observed between the root and periphery of each lobe. They concluded that delivery was more effective and consistent using the surfactant than using saline as a vehicle. Chen et al35 conducted a study to evaluate pulmonary responses to intratracheal administration of surfactant with and without steroid in rats with paraquat-induced lung injury. They concluded that the combined administration of high doses of intratracheal surfactant and steroid improved gas exchange; ameliorated lung inflammation, as demonstrated by the lower levels of protein and tumor necrosis factor-␣ in the tracheal aspirates; and alleviated morphologic lung damage. Surfactant alone had a lesser effect on these parameters.34 e1316

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The earlier studies from Patole et al36 and from our group18 in human neonates using intratracheal budesonide without surfactant as vehicle did not show better improvement as compared with the saline control group, possibly either because of inadequate dosage (0.02 and 0.05 mg in the study by Patole et al36) or because of poor distribution of budesonide in the lungs. Similar to inhaled budesonide, most of the intratracheal medication without using surfactant as vehicle is probably remaining in the airway and absorbed in the airways even before they reach the peripheral lung.11–17 In both studies, however, the adverse effects ascribed to steroids were not significantly higher than those in the control group. All of these studies suggested that a combined use of surfactant and a higher dose of steroid may be more effective in delivery of the medication and, consequently, may be more beneficial. There are, however, certain concerns about the interaction between surfactant and steroid, because the function of surfactant may be affected not only by its distribution in the lung but also by its metabolism in the tissue level. We do not know whether budesonide would affect surfactant metabolism, absorption, and cycling in the lungs. Nevertheless, our study indicates that intratracheal instillation of budesonide-surfactant has a better pulmonary outcome than instillation of surfactant alone. The mechanism for the improvement can be speculated. Budesonide is well known for its strong local anti-inflammatory effect.24,25,35 After budesonide inhalation or intratracheal instillation, there were significant decreases in the inflammatory cell, protein, and cytokines in lung lavage in children and rats.25,35 Budesonide may also increase cardiac stroke volume, similar to what was seen after dexamethasone therapy,37 and may stabilize the blood pressure. In our study, the blood pressure was significantly higher in the treated group as compared with the control group on days 3 to 5, but the blood pressure was still within the reference ranges for the infant.38 This later effect of budesonide on the stabilization of blood pressure may be beneficial to the infant. It is also interesting to note that, as compared with that following systemic steroid administration,1,8 intratracheal instillation of budesonide caused a faster response on pulmonary status. The direct local effect of budesonide on the lung must play an important role for the fast improvement. Whatever the mechanisms are, the immediate pulmonary improvement and subsequent improvement in cardiopulmonary status seem to be responsible for the better outcome. The results of our study also suggest that a similar therapeutic method may be applied to other pulmonary diseases, such as shock lung, pneumonia, severe acute respiratory syndrome, or malignancy. The systemic adverse effects associated with steroids, antibiotics, and chemotherapeutic agents would be markedly reduced. The present study also indicated that, after instillation of the budesonide-surfactant mixture, budesonide can be delivered to the lung and remain in the lung. Although we did not measure all of the metabolites and the amount of budesonide excreted in urine, the AUC during the first 8 hours suggested that a large proportion of budesonide may still remain in the lungs. This finding is

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consistent with the report by Van Den Bosch et al,39 which stated that, after budesonide inhalation, the plasma concentration of budesonide was only one eighth of that in the lung tissue. After instillation of the budesonide-survanta mixture, survanta may enhance solubilization of budesonide and may increase budesonide absorption into cells.40,41 Once budesonide is absorbed, it can be conjugated extensively with fatty acids, resulting in the formation of budesonide ester at the C21-hydroxyl group.42 This conjugation process is reversible, and the conjugates can be hydrolyzed intracellularly, gradually releasing free budesonide into the surrounding medium. This release takes ⱕ10 hours in vitro.43 Budesonide is not metabolized in lung cells.42 The reversible conjugation may improve airway selectivity, as well as prolong the local anti-inflammatory action in the airways. Perhaps this will explain why budesonide was effective for days, although only 1 or 2 doses were instilled in our study. The topical anti-inflammatory effect of budesonide is well established, and its potency is much higher than that of beclomethasone dipropionate, prednisone, and hydrocortisone.25,43 The terminal half-life of plasma budesonide is 4.13 hours, much shorter than most of the other medications reported in premature infants. The short half-life and the simultaneous increases in 16␣-hydroxyprednisolone indicated that budesonide is metabolized fast in the liver or other tissue. The systemic effect of 16␣-hydroxyprednisolone is minimal.25,43 CONCLUSIONS We conclude that early intratracheal instillation of budesonide using surfactant as a vehicle significantly improved the combined outcome of death or CLD. The number of survivors without CLD increased. There were no apparent immediate and clinically significant adverse effects. However, this study was done on a small number of infants; the sample size was determined based on the hypothesis that a large proportion of infants (50%) would have improved. This hypothesis may not be realistic but was convenient for a pilot study. Our sample size was not large enough to exclude all of the possible size effects; we estimated that it would take ⬎10 years to complete the study to solve these problems. A large sample, multicenter study is, therefore, needed, and we believe it is warranted. In view of the fact that the majority of the treated infants received only 1 dose of budesonide, the long-term adverse effect would most likely be negligible. The long-term outcomes of this study are being investigated. ACKNOWLEDGMENTS This study was supported in part from the National Science Council Taipei (NSC-94-2314-B-039-004 Taiwan). We are indebted to Dr Hsin Y. Hsieh, the independent observer for monitoring the study; Dr Norman Jacob for reviewing the article; and S. Y. Chen, Y. C. Pan, and Melanie Li-Kastanes for article preparation.

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Early Intratracheal Instillation of Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants: A Pilot Study Tsu F. Yeh, Hong C. Lin, Chien H. Chang, Tien S. Wu, Bai H. Su, Tsai C. Li, Suma Pyati and Chang H. Tsai Pediatrics 2008;121;e1310-e1318; originally published online Apr 21, 2008; DOI: 10.1542/peds.2007-1973 Updated Information & Services

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